Doub et al. in U.S. Pat. No. 2,517,772 describes the impregnation of neutralized oxidized cellulose products with thrombin. Doub et al. discloses a method of neutralizing oxidized cellulose cloth with an aqueous sodium bicarbonate solution (Example 2) or an aqueous calcium acetate solution (Example 1). Example 2 of the Doub et al. patent discloses neutralizing oxidized cellulose gauze with an aqueous solution of strongly basic sodium bicarbonate and then impregnating the neutralized product with thrombin. The thrombin impregnated gauze is then frozen and dried from the frozen state to allegedly provide a highly hemostatic surgical dressing.
The present inventors have found that utilization of aqueous solutions of sodium bicarbonate to neutralize oxidized cellulose cloth results in a cloth that is partially gelled, distorted from its original size and very weak with little integrity. The tensile strength of the cloth is too low for practical use such as, for example, a hemostat.
Study of oxidized cellulose cloth that has been neutralized with calcium acetate in accordance with the teachings of Example 1 of the Doub et al. patent provided a cloth that is of acceptable integrity but is irritating to mammalian skin and other body cells at point of contact. Further, large, whitish masses presumed to be granuloma tissue formed at the application site of the cloth. Apparently, such tissue is attempting to encapsulate the calcium salt of the oxidized cellulose cloth. The patent to Doub et al. does not disclose any practical data pertaining to testing in animals.
The present inventors have found that the use of strongly basic aqueous sodium hydroxide, ammonium hydroxide, and sodium carbonate solutions to neutralize oxidized cellulose cloth all lead to considerable shrinkage and loss of tensile strength to the cloth. The use of dry ammonia gas produces a pronounced browning of the cloth and rapid gelation of the cloth when it is wetted thus making it impractical for use as a therapeutic product such as a surgical dressing.
Barinka et al. in British Pat. 1,593,513 disclose a process for oxidizing cellulose with a mixture of nitric acid and stabilized ("phlegmatized") sodium nitrite. The material is then stabilized with an aqueous-alcoholic solution of urea or its N,N-disubstituted alkyl or acyl derivatives. Finally, the oxidized cellulose is converted to its calcium, sodium, or ammonium salt by repeatedly alternating absorption-in and centrifuging-off a solution of an equimolar mixture of chloride and acetate of calcium, sodium or ammonium.
Oxidized cellulose fabrics are bioresorbable and absorbent matrices capable of convenient application to tissue surfaces. Two examples of such a fabric are INTERCEED* (TC7) Absorbable Adhesion Barrier and SURGICEL* Absorbable Hemostat. However these materials are acidic. The PH of the aqueous phase of 1 g of INTERCEED Barrier suspended in 100 ml of purified water is approximately 4.1. The surface PH of a fully water-saturated piece of fabric is about 1.7. Materials such as thrombin, tissue plasminogen activator analogue (t-PAA), and other highly acid-sensitive materials are inactivated immediately on such a matrix, Precluding their use for delivery to the site of implantation at the time of surgery. At this pH an active agent such as heparin does not lose its activity immediately, thus allowing delivery at the time of, or shortly before surgery, but will be inactivated over time. This precludes the use of INTERCEED Barrier impregnated with heparin as a patient ready storage-stable product.
It is therefore an object of the present invention to provide a storage stable neutralized oxidized cellulose cloth with a PH of from 5 to 8, which retains its integrity and tensile strength for practical use and therapeutic application and can advantageously be impregnated with acid-sensitive medicaments, biologics, enzymes, and adhesion-preventive substances.